The goal of this project is to study the epigenetic basis of chronic pain, with a specific emphasis on understanding the epigenetic mechanisms active during the transition from acute pain to chronic neuropathic pain. Chronic pain leads to prolonged suffering and a reduced quality of life for millions of Americans. Neuropathic pain remains a major clinical problem and therapeutic challenge because existing analgesics are often ineffective and can cause serious side effects. In addition, the mechanisms involved in the sustained alterations in gene expression found in primary sensory neurons and their role in the transition from acute to chronic pain are still poorly understood. One of the characteristic changes in neuropathic pain is the persistent reduction in the expression and function of certain voltage-activated K+ (Kv) and Ca2+-activated K+ channels in dorsal root ganglion (DRG) neurons. Down regulation of Kv1.4, Kv4.2, or large-conductance Ca2+-activated K+ (BK) channels can increase the excitability of DRG neurons, which causes a persistent increase in abnormal nociceptive input and chronic pain. One possibility is that these genes are down regulated by epigenetic changes. Despite the significant advances being made in understanding the role of epigenetics in regulating genes involved in developmental biology and cancer, little is known about the importance of epigenetic changes in the development of chronic pain. In this collaborative and multi-disciplinary project, Dr. Hui-Lin Pan, a neuroscientist with expertise in neural plasticity and neuropathic pain, and Dr. Jean-Pierre Issa, an expert in epigenetics, will collaborate and identify epigenetic changes in the DRG in neuropathic pain. We will test the overall hypothesis that epigenetic mechanisms contribute to the neuroplasticity in primary sensory neurons that is involved in the induction, development, and maintenance of chronic neuropathic pain. The specific aims of this application are to (1) identify changes in DNA methylation and histone modifications of Kv1.4, Kv4.2, and BK genes in the DRG during neuropathic pain development;(2) identify genome-wide patterns of DNA methylation and histone modifications in the DRG during neuropathic pain development;and (3) determine the effects of epigenetic modulation on the development of chronic neuropathic pain and the associated silencing of K+ channel genes in the DRG. Because the critical role of epigenetic mechanisms in the regulation of gene expression and development of neuropathic pain has not been recognized previously, our use of epigenetic approaches to answer these questions could transform our knowledge of how the epigenome defines and contributes to chronic pain development. We expect that new findings from this proposal will provide novel insight into the epigenetic control of chronic pain development and greatly improve our understanding of the molecular pathways that regulate neuroplasticity in chronic pain. In addition, our project may provide novel information, which could lead to the development of new epigenetic therapeutic agents to prevent and treat chronic neuropathic pain. PUBLIC HEALTH RELEVANCE: Chronic neuropathic pain is a major clinical problem because available pain medications are less effective and possess serious side effects. Epigenetic codes include patterns of DNA methylation and histone modifications that regulate the expression of various gene products. This application seeks to define whether epigenetic mechanisms are involved in the development of chronic neuropathic pain. Findings from this proposal not only are critical to significantly improve our understanding of the molecular mechanisms of neuropathic pain but also are important to the development of new strategies to prevent and treat chronic pain.